The present invention pertains to the novel compounds of Formula I and the use of such compounds as testosterone-5.alpha.-reductase inhibitors.
It is well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo. 2 (1972). However. these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It more recently became known in the art that the principal mediator of androgenic activity in some target organs is 5.alpha.-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh et al , Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17.beta.-carboxylate was a testosterone-5.alpha.-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17.beta.-carboxylic acid are both active inhibitors of testosterone-5.alpha.-reductase in vitro. They further demonstrated that topical application of either testosterone or 5.alpha.-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17.beta.-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5.alpha.-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5.alpha.-reductase.
Recently, a number of investigators have published regarding the biological activity of 5.alpha.-reductase inhibitors. See for example, Brooks, et al., The prostate 9: 65-75 (1986), Liang et al., Endrocrinology 117, No. 2, pp. 571-579 (1985), Rasmusson et al., J. Med. Chem. 27: 1690-1701 (1984), Liang et al., J. Biol. Chem. 259, No. 2, pp 734-739 (1984). However, the compounds of the present invention have quite distinct structures from those previously reported for testosterone-5.alpha.-reductase inhibitors.
The compounds of Formula I are sterol inhibitors of testosterone-5.alpha.-reductase. While 4,19-oxygen bridged cholestanes have been reported in the literature [F. Turecek and P. Kocovsky, Coll. Czech. Chem. Comm. 45, 274-293 (1980); P. Kocovsky, Coll. Czech. Chem. Cmmun. 45, 3008-3022 (1980)], these compounds are not sterols nor are they shown to be inhibitors of 5.alpha. reductase.